These studies are directed toward the elucidation of the joint contracture process in biochemical, bioengineering, and morphologic terms, and toward the development of therapeutic programs which will minimize contracture formation. Major changes in the composition of fibrous connective tissue have been demonstrated in experimental joint contractures as a result of immobilization. These changes were uniformly observed in ligaments, tendons, fascia and capsular tissue of the knee joint. Significant correlations between measures of strength of contracture and reduction in contracture and reduction in content of glycosaminoglycans (e.g. hyaluronic acid) and water in the connective tissue matrix were shown. A working hypothesis was constructed to explain these observations. The loss of water and glycosaminoglycans in the periarticular connective tissue of immobilized joints contributes to changes in the physical characteristics of the affected joints. Presumably, this role is a permissive one, allowing closer proximity of critical intercept points in the immobilized fibrous connective tissue matrix which allows cross-links through one of two mechanisms: a) random disposition of newly synthesized collagen or b) covalent cross-links between pre-existing fibers. Present data shows 2-fold increases of DHLNL (Dihydroxysinonorleucine) in immobilized connective tissue. Under this formulation, the fixed posture at the intercept points translates into restriction of motion in the joint composite. It was possible to reduce the strength of contracture by D-penicillamine and by estradiol in pharmacological doses. In the next phase of this work we will concentrate on the development of optimum schedule of estradiol and D-penicillamine administration. Time sequence of collagen and reducible labile imminium Schiff base cross-links or keto-imine forms will be studied during the period of immobilization.